LINUS PAULING INSTITUTE RESEARCH REPORT

Chemoprevention of Colon Cancer

Gayle Orner, Ph.D.
LPI Research Assistant Professor

Summary:
Special mutant mouse strains that develop colon cancer were used to investigate
the prophylactic effect of various teas and/or a non-steroidal anti-inflammatory
drug called sulindac. The combination of white tea plus sulindac was most
effective in decreasing the number of colon tumors in mice.

The non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin,
the anti-arthritis drug sulindac, and the newer, more selective drugs
like Celebrex®, show great
promise for the prevention of colon cancer. NSAIDs are effective chemoprevention
agents in genetically predisposed and chemically-induced animal models
of intestinal cancer, and high aspirin intake is associated with a 40-50%
decrease in colon cancer mortality in humans. Although potent chemopreventive
agents, some conventional NSAIDs can cause severe side-effects, including
gastrointestinal (GI) bleeding, GI perforation, renal toxicity, and even
death. NSAIDs are responsible for at least 100,000 hospitalizations and
10,000 to 20,000 deaths annually and are responsible for more serious
adverse drug reactions reported to the FDA than any other class of drugs.
These adverse effects are generally dose-dependent, with higher doses
more likely to cause toxicity.

One strategy to minimize toxicity and increase efficacy of NSAIDs is to
use very low doses of these drugs in combination with other chemopreventive
agents. Natural products like tea may be effective in combined chemo-
prevention strategies. Support from a Linus Pauling Institute pilot project
grant allowed us to test tea alone and in combination with the NSAID sulindac
for effectiveness against intestinal cancer in mice.

Familial
adenomatous polyposis (FAP), a hereditary condition that predisposes affected
people to colon cancer, is caused by a mutated adenomatous polyposis coli
(APC) gene. FAP patients develop hundreds to thousands of colonic polyps,
beginning at about 16-years old. Without treatment, the disease progresses
to colorectal cancer. The NSAID sulindac has been shown to cause regression
of polyps in FAP patients. However, the drug is not effective as a sole
treatment for FAP because drug resistance occurs, and cancer has developed
in patients while being treated with sulindac. Instead, the primary treatment
for FAP remains the surgical removal of the colon, typically when patients
are in their late teens or early 20s. A special strain of mice, called
Apcmin mice, have a mutation in the same gene that
causes FAP and, like FAP patients, these mice develop large numbers of
intestinal tumors at an early age. Apcmin mice have
been useful for testing pharmaceuticals and natural products that may
be useful for the treatment of FAP. In the first part of our pilot project,
we tested tea alone and in combination with sulindac in Apcmin mice to
find out if these substances protected against the development of colon
cancer.

Apcmin mice
were given either green or white tea in their drinking water for 12 weeks.
White tea is minimally processed, whereas green tea has been withered
and then fired or steamed, resulting in more oxidized constituents. Black
tea, commonly consumed in the U.S., is the most processed and oxidized
tea—it has been withered, fully fermented, and fired. Teas were
prepared by adding 1.5 grams of tea to 100 milliliters of boiling water
and allowing the teas to steep for 2 minutes, which produces a tea concentration
similar to that typically consumed by people. Other Apcmin mice were given
a low dose of sulindac or a combination of white tea plus sulindac. Apcmin
mice treated with sulindac, green tea, or white tea had only half the
number of tumors as did the control group of Apcmin mice. Mice treated
with the combination of white tea plus sulindac had fewer tumors than
the mice given either tea or sulindac alone. Indeed, the protection provided
by a combination of white tea plus low-dose sulindac was equivalent to
what has been reported for double this concentration of sulindac. Therefore,
tea may be a useful complementary treatment for FAP.

Hereditary
cancers like those occurring in individuals with FAP account for only
a small percentage of human colon cancers. Most human colon cancers are
considered sporadic in origin, arising from some combination of genetics,
environment, and lifestyle. Another strain of mice that may be well suited
to study for sporadic colorectal cancer was developed by Dr. Matthias
Ernst of the Ludwig Institute for Cancer Research in Australia. These
mice, known as A33DNb-cat
mice, contain a mutation in a gene coding for b-catenin,
which is a protein that controls a key signaling pathway frequently disrupted
in human colon cancers. While A33DNb-cat
mice do not develop large numbers of tumors spontaneously, they are highly
susceptible to chemically-induced colon cancer. In the second part of
our project, we tested white tea alone and in combination with sulindac
in this mouse model of sporadic colon cancer. In contrast to our results
in Apcmin mice, white tea and sulindac alone did not
inhibit tumor formation in A33DNb-cat
mice at the concentrations we used. However, the combination of white
tea plus sulindac significantly inhibited tumor formation in A33DNb-cat
mice. Therefore, the combination of white tea plus sulindac was effective
in mouse models of both hereditary and sporadic intestinal cancer.

We now have
funding from the National Cancer Institute and the National Center for
Complementary and Alternative Medicine to conduct additional studies that
may help to move this promising combination of white tea and sulindac
into human clinical trials.